The intermediate processes which couple or transduce the interaction of an effector molecule (e.g., ADP, epinephrine, 5-hydroxytryptamine, etc.) with the platelet membrane into the platelet are unknown. While each of the effector molecules mentioned may have a unique interaction with the platelet membrane they can be generalized as interacting with platelet receptors to induce an increase intraplatelet calcium ion levels. The increase in platelet Ca 2plus ion induces the onset of funcional change. As in most cell exhibiting excitation-contraction coupling, the intermediate processes are likely to consist of inward ion movements; e.g., influx of external Ca 2 plus, influx of Na plus. We were the first to demonstrate that ADO addition to human platelets in plasma induces inward movement of Na plus but not Ca 2 plus. On the other hand, epinephrine addition induces inward movement of Ca 2 plus but not Na plus. Furthemore, addition of amiloride will inhibit the inward movement of Na plus and aggregation induced by ADO. Verapamil added to resuspended platelets inhibits the epinephrine response and Ca 2 plus influx but not the ADP response. Thus, the effector response is ion-specific. Our findings have led us to postulate that the ADP excitation-coupling mechanism consists of an increase in Na permeability, a dissipation of the Na plus or minus electrochemical transmembrane gradient, associatied with the inward movement of Na plus and a rise in intraplatelet Na plus. The rise in intraplatelet Na plus acts to induce intraplatelet calcium redistribution in a manner analogous to muscle. If this view is held it follows that platelet sensitivity to ADP will be a function of the Na plus transmembrane gradient and the rate of Na plus efflux (thus, we found that ouabain, which blocks Na plus efflux induces hypersensitivity to aDP). We propose to further delineate the characteristics of ADP (and other agonists, e.g., 5-HT) induced inward movement of Na plus and to relate these characteristics to the induction of functional change.